Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections

doi:10.1016/j.ejmech.2017.12.090

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	Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections
	Wei, Hanwen 1; Mao, Fei 1; Ni, Shuaishuai 1; Chen, Feifei 2; Li, Baoli 1; Qiu, Xiaoxia 1; Hu, Linghao 1; Wang, Manjiong 1; Zheng, Xinyu 1; Zhu, Jin 1
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-02-10
卷号	145 页码:235-251
关键词	CrtN inhibitor STX biosynthesis Pigment inhibitory activity Resistant S. aureus
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.12.090
文献子类	Article
英文摘要	Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H2O2 killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271. (C) 2018 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[21672064] ; National Key R&D Program of China[2017YFB0202600] ; "Shu Guang" project - Shanghai Education Development Foundation[14SG28] ; "Shu Guang" project - Shanghai Municipal Education Commission[14SG28] ; Shanghai Sailing Program[17YF1403600] ; Fundamental Research Funds for the Central Universities[00000000]
WOS关键词	MRSA INFECTIONS ; VIRULENCE ; EPIDEMIOLOGY ; CRTN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000425198200019
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279905]
专题	药理学第三研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Lan, Lefu; Li, Jian
作者单位	1.East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Mei Long Rd, Shanghai 200237, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Wei, Hanwen,Mao, Fei,Ni, Shuaishuai,et al. Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,145:235-251.
APA	Wei, Hanwen.,Mao, Fei.,Ni, Shuaishuai.,Chen, Feifei.,Li, Baoli.,...&Li, Jian.(2018).Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,145,235-251.
MLA	Wei, Hanwen,et al."Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 145(2018):235-251.